Process for the preparation of 3-(3-chloro-1h-pyrazol-1-yl)pyridine

ABSTRACT

This disclosure relates to the field of preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine and intermediates therefrom. These intermediates are useful in the preparation of certain pesticides.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/049,537, filed Sep. 12, 2014, the entiredisclosure of which is hereby expressly incorporated by reference intothis Application.

TECHNICAL FIELD

This disclosure relates to the field of preparation of3-(3-chloro-1H-pyrazol-1-yl)pyridine and intermediates therefrom. Theseintermediates are useful in the preparation of certain pesticides.

BACKGROUND

US 20130288893(A1) describes certain(3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and theiruse as pesticides. The processes therein to prepare these amides andcarbamates result in low yields, rely on a starting material that isdifficult to prepare (3-chloropyrazole), and provide a product that isdifficult to isolate in a pure form. It would be desirable to have aprocess for preparing 3-(3-chloro-1H-pyrazol-1-yl)pyridine that avoidsthese problems.

DETAILED DESCRIPTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains.

As used herein, the term “alkoxide” means an alkyl further consisting ofa carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, and tert-butoxy.

The present disclosure provides an alternative process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by cyclizing3-hydrazinopyridine•dihydrochloride with an alkyl methacrylate toprovide 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1), by chlorinating(1) to provide 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine(2), by oxidizing (2) to provide3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3), by further oxidizing(3) to provide 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid(4), and by decarboxylating (4) to provide3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b).

Thus, the present disclosure concerns a process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

which comprises

-   -   a) cyclizing 3-hydrazinopyridine•dihydrochloride

-   -    with alkyl methacrylate,

-   -    wherein R represents (C₁-C₄) alkyl,    -    in a (C₁-C₄) alkyl alcohol at a temperature of about 25° C. to        about 80° C. in the presence of an alkali metal (C₁-C₄) alkoxide        to provide 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1)

-   -   b) chlorinating 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1)        with a chlorinating reagent in an organic solvent at a        temperature of about 25° C. to about 100° C. to provide        3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2)

-   -   c) oxidizing        3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2)        with an oxidant in a solvent at a temperature of about 25° C. to        about 100° C. to provide        3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3)

-   -   d) further oxidizing        3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3) with an        oxidant in a polar protic solvent at a temperature of about        50° C. to about 100° C. to provide        3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4)

and

-   -   e) decarboxylating        3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) with        copper oxide in a polar aprotic solvent at a temperature of        about 80° C. to about 180° C. to provide        3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b).

Scheme 1 outlines this process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b).

In step 1a, 3-hydrazinopyridine•dihydrochloride is cyclized with a(C₁-C₄) alkyl methacrylate, in a solution further comprising a (C₁-C₄)alkyl alcohol and an alkali metal (C₁-C₄) alkoxide, to provide4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1). Step a is conducted at atemperature from about 25° C. to about 80° C. While stoichiometricamounts of 3-hydrazinopyridine•dihydrochloride and (C₁-C₄) alkylmethacrylate may be used, it is often convenient to use about a 1.5 foldto about a 2 fold excess of (C₁-C₄) alkyl methacrylate compared to3-hydrazinopyridine•dihydrochloride. The (C₁-C₄) alkyl alcohol ispreferably selected from methanol, ethanol, propanol, butanol, andmixtures thereof. The alkali metal (C₁-C₄) alkoxide is preferablyselected from sodium methoxide, sodium ethoxide, and mixtures thereof.It is often convenient to use about a 2 fold to about a 3 fold excess ofalkali metal (C₁-C₄) alkoxide compared to3-hydrazinopyridine•dihydrochloride. Furthermore, it is most preferredif sodium ethoxide and ethanol is used.

In another embodiment, 3-hydrazinopyridine•dihydrochloride is cyclizedwith methyl methacrylate in the presence of sodium ethoxide and ethanoland this mixture is heated at about 50° C. The crude4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1) is used as is withoutfurther purification or isolation.

In step 1b, 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1) ischlorinated with a chlorinating reagent in an organic solvent at atemperature from about 25° C. to about 100° C. to provide3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2). Suitablechlorinating reagents include phosphoryl chloride (phosphorousoxychloride), phosphorus pentachloride, and mixtures thereof. Phosphorylchloride is currently preferred. It is often convenient to use about a1.1 fold to about a 10 fold excess of the chlorinating reagent comparedto 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1). The chlorination isperformed in an organic solvent that does not substantially react withthe chlorinating reagent. Suitable solvents include nitriles such asacetonitrile. It is currently preferred to use phosphoryl chloride asthe chlorinating reagent and acetonitrile as the solvent.

In another embodiment, 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1) inacetonitrile is chlorinated with phosphoryl chloride and the mixture isheated to about 75° C. The3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2) can beisolated and purified by standard techniques.

In step 1c, 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine(2) is oxidized with an oxidant in an organic solvent at a temperatureof about 25° C. to about 100° C. to provide3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3). Suitable oxidantsinclude copper (I) chloride in the presence of oxygen, potassiumferricyanide, and manganese (IV) oxide. It is often convenient to useabout a 1.5 fold to about a 15 fold excess of oxidant compared to3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2). Theoxidation is performed in a solvent that does not substantially reactwith the oxidant. Suitable solvents include water,N,N-dimethylformamide, N-methylpyrrolidinone, dichloromethane,tert-butanol, nitriles such as acetonitrile, aromatic hydrocarbons suchas toluene, and mixtures thereof. It is currently preferred to usecopper (I) chloride in the presence of oxygen as the oxidant, withN,N-dimethylformamide, N-methylpyrolidinone, and mixtures thereof as thesolvent. It is also preferred to use potassium -ferricyanide as theoxidant, with water as the solvent. It is also preferred to usemanganese (IV) oxide as the oxidant, with dichloromethane, tert-butanol,acetonitrile, toluene, and mixtures thereof as the solvent. It is alsopreferred to use manganese (IV) oxide as the oxidant, with acetonitrileas the solvent.

In another embodiment,3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2) inacetonitrile is oxidized with manganese (IV) oxide and the mixture isheated at about 40° C. The 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine(3) can be isolated and purified by standard techniques.

In step 1d 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3) is furtheroxidized with an oxidant in a protic solvent at a temperature of about50° C. to about 100° C. to provide3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4). Suitableoxidants include potassium permanganate and sodium permanganate. It isoften convenient to use about a 2.5 fold to about a 4.5 fold, preferablyabout a 3.0 fold excess of oxidant compared to3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3). The oxidation isperformed in a protic solvent that does not substantially react with theoxidant. Suitable solvents include water, tert-butanol, tert-amylalcohol, and mixtures thereof.

In another embodiment, 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3)is further oxidized by sodium permanganate in water and tert-butanol andheated at about 80° C. The3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) can beisolated and purified by standard techniques.

In step 1e, 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4)is decarboxylated in the presence of copper oxide which may optionallybe ligated with a bidentate ligand such as tetramethyl ethylenediaminein a polar aprotic solvent at a temperature from about 80° C. to about180° C. to provide 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). Suitablecopper oxide sources include copper (I) oxide and copper (II) oxide aswell as mixtures thereof. It is convenient to use about 5 wt % to about20 wt % of copper oxide based on3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4). Suitablesolvents include N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, and mixtures thereof.

In another embodiment,3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4) and copper(I) oxide are mixed with N,N-dimethylacetamide and heated to about 125°C. The 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) can be isolated andpurified by standard techniques.

An illustrative example of how 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)may be used for preparing certain pesticidal(3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides is outlined in Scheme 2.

In step 2a, 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) is nitrated withnitric acid (HNO₃), preferably in the presence of sulfuric acid (H₂SO₄)to yield 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6). Thenitration may be conducted at temperatures from about −10 ° C. to about30° C.

In step 2b, 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6) isreduced to yield 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (2-7). Forexample, 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6) may bereduced with iron in acetic acid (AcOH).3-(3-Chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6) may also be reducedwith iron and ammonium chloride (NH₄Cl). Alternatively, this reductionmay be carried out using other techniques in the art, for example,3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6) may be reduced usingpalladium on carbon in the presence of hydrogen (H₂). This reaction maybe conducted at temperatures from about −10° C. to about 30° C.

In step 2c, 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (2-7) isacylated with acetylating agents such as acetyl chloride or aceticanhydride, preferably acetic anhydride (Ac₂O) to yieldN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2-8). Theacylation is conducted in the presence of a base, preferably aninorganic base, such as, sodium bicarbonate (NaHCO₃), and preferably, apolar solvent, such as ethyl acetate and/or tetrahydrofuran. Thisreaction may be conducted at temperatures from about −10 ° C. to about30° C.

In step 2d, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2-8)is alkylated with ethyl bromide (EtBr) in the presence of a base, suchas sodium hydride (NaH) or sodium tert-butoxide (NaOt-Bu), in a polaraprotic solvent, such as tetrahydrofuran, at temperatures from about 20°C. to about 40° C., over a period of time of about 60 hours to about 168hours, to yieldN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (2-9). Ithas been discovered that use of an iodide additive, such as potassiumiodide (KI) or tetrabutylammonium iodide (TBAI) can decrease the timenecessary for the reaction to occur to about 24 hours. It has also beendiscovered that heating the reaction at about 50° C. to about 70° C. ina sealed reactor (to prevent loss of ethyl bromide) also decreases thereaction time to about 24 hours.

In step 2e,N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-ye-N-ethylacetamide (2-9) istreated with hydrochloric acid in water at temperatures from about 50°C. to about 90° C., to yield3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (2-10). Steps d and eof Scheme 2 may also be performed without the isolation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl-N-ethylacetamide (2-8).

In step 2f, 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (2-10) isacylated with 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride in thepresence of a base preferably, sodium bicarbonate to yield pesticidal(3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amide (2-11). The reaction mayalso be conducted in the absence of a base to yield pesticidal(3-halo-1-(pyridin-3-y1)-1H-pyrazol-4-yl)amide (2-11).

In step 2g, pesticidal (3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amide(2-11) is oxidized with hydrogen peroxide (H₂O₂) in methanol to yieldpesticidal (3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amide (2-12).

EXAMPLES

These examples are for illustration purposes and are not to be construedas limiting the disclosure to only the embodiments disclosed in theseexamples.

Starting materials, reagents, and solvents that were obtained fromcommercial sources were used without further purification. Anhydroussolvents were purchased as Sure/Seal™ from Aldrich and were used asreceived. Melting points were obtained on a Thomas Hoover Unimeltcapillary melting point apparatus or an OptiMelt Automated Melting PointSystem from Stanford Research Systems and are uncorrected. Examplesusing “room temperature” were conducted in climate controlledlaboratories with temperatures ranging from about 20° C. to about 24° C.Molecules are given their known names, named according to namingprograms within ISIS Draw, ChemDraw or ACD Name Pro. If such programsare unable to name a molecule, the molecule is named using conventionalnaming rules. ¹H NMR spectral data are in ppm (δ) and were recorded at300, 400 or 600 MHz; ¹³C NMR spectral data are in ppm (δ) and wererecorded at 75, 100 or 150 MHz, and ¹⁹F NMR spectral data are in ppm (δ)and were recorded at 376 MHz, unless otherwise stated.

1. Preparation of 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1)

To a 250 mL three-neck round bottom flask equipped with a refluxcondenser was introduced 3-hydrazinopyridine•dihydrochloride (15.0 g,82.4 mmol). Sodium ethoxide (21 wt % in ethanol, 92.3 mL, 247 mmol) wasadded over 5 minutes and the pot temperature increased from 23° C. to38° C. The resultant light brown-slurry was stirred for 10 minutes.Methyl methacrylate (17.7 mL, 165 mmol) was added slowly over 15 minutesand the pot temperature remained at 38° C. The yellow mixture wasstirred at 50° C. under nitrogen for 4 hours. The mixture was thencooled down to 10° C. and hydrochloric acid (4 M in 1,4-dioxane, 20.6mL) was added slowly to quench excess base leading to a light brownsuspension. The mixture was concentrated under reduced pressure toafford the title compound as a brown solid as a mixture with sodiumchloride (35.2 g, 241%): EIMS m/z 177 ([M]⁺). The crude material wasused directly in the next step.

2. Preparation of3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2)

Crude 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (35.2 g, ˜82.4 mmol)was introduced into a 250 mL three-neck round bottom flask equipped witha reflux condenser. Acetonitrile (100 mL) was then added. To this yellowmixture was added phosphoryl chloride (11.56 mL, 124 mmol) slowly. Theyellow slurry was stirred at 75° C. for 1 hour. The mixture was cooleddown and concentrated to remove volatiles. The brown residue wascarefully quenched with water (120 mL), and basified with NaOH (50 wt %in water) to pH 10 while keeping the temperature below 60° C. Themixture was then extracted with ethyl acetate (3×150 mL). The combinedorganic extracts were washed with water (80 mL) and concentrated underreduced pressure to afford the crude product as dark purple oil. Thecrude product was purified by flash column chromatography using 0-70%ethyl acetate/hexanes as eluent to provide the title compound as a brownoil (12.3 g, 76% over two steps): ¹H NMR (400 MHz, CDCl₃) δ 8.27 (dd,J=2.8, 0.7 Hz, 1H), 8.15 (dd, J=4.6, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.9,1.4 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.17-4.06 (m, 1H), 3.47(t, J=8.9 Hz, 1H), 3.44-3.34 (m, 1H), 1.37 (d, J=6.8 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 148.17, 142.07, 141.10, 134.74, 123.39, 119.92,56.62, 43.62, 16.16; EIMS m/z 195 ([M]⁺).

3. Preparation of 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3)

To a solution of3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (1.0 g, 5.0mol) in acetonitrile (10.0 mL) at 0° C. was added manganese(IV) oxide(1.3 g, 15 mmol) portionwise over 10 minutes. The mixture was slowlywarmed to 22° C. over 40 minutes and then heated to 40° C. overnight.After 20 hours, additional manganese (IV) oxide (0.44 g, 5.0 mmol) wasadded in one portion and the mixture was stirred for 1 hour. The mixturewas cooled down and filtered. The filter cake was washed withacetonitrile (3×15 mL). The organic filtrate was dried and concentratedto afford the title compound as a light yellow solid (0.92 g, 95%): ¹HNMR (400 MHz, CDCl₃) δ 8.90 (dd, J=2.6, 0.8 Hz, 1H), 8.52 (dd, J=4.8,1.5 Hz, 1H), 7.99 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.74 (q, J=0.9 Hz, 1H),7.39 (ddd, J=8.3, 4.8, 0.8 Hz, 1H), 2.13 (d, J=0.9 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 147.26, 142.87, 139.53, 135.90, 126.53, 125.69, 123.84,116.86, 22.47; EIMS m/z 193 ([M]⁺).

4. Preparation of 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylicacid (4)

To a mixture of3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2.0 g, 10mmol) in water (10.0 mL) and tert-butanol (5.0 mL) was added a solutionof sodium permanganate (NaMnO4) (5.0 g, 35 mmol) in water (15 mL) over20 minutes. The mixture was heated to 80° C. and stirred overnight.Additional sodium permanganate (0.711 g, 5.0 mmol) in water (2.0 mL) wasadded after 16 hours and the mixture was stirred for another 4 hours.The dark mixture was filtered through Celite®, washed with water (5.0mL) and ethyl acetate (3×15 mL). The aqueous layer was extracted withethyl acetate (25 mL) and acidified with concentrated hydrochloric acidto pH 5 leading to white precipitate which was collected by filtration.The filtrate was concentrated leading to white precipitate which wascollected by filtration and washed with water (2.0 mL). The solidproducts were combined and dried under high vacuum to afford the titlecompound as a white solid (1.0 g, 46%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.11(s, 2H), 8.59 (d, J=4.7, 1H), 8.28 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.58(dd, J=8.0, 4.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 162.24, 148.35,141.46, 140.21, 135.01, 134.01, 126.45, 124.23, 115.34; ESIMS m/z 224([M+H]⁺).

5. Preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

To a mixture of 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid(0.223 g, 1.0 mmol) in N,N-dimethylacetamide (3.0 mL) was added copper(I) oxide (0.022 g, 10 wt %). The mixture was heated to 125° C. andstirred for 6 hours. The brown mixture was filtered and washed withN,N-dimethylacetamide (1.0 mL) and acetonitrile (2×2 mL). The lightyellow filtrate was analyzed by LC using di-n-propyl phthalate asinternal standard (0.124 g, 69% in-pot yield); mp 66-68° C.; ¹H NMR (400MHz, CDCl₃) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02(ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m,1H), 6.45 (d, J=2.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 148.01, 142.72,140.12, 135.99, 128.64, 126.41, 124.01, 108.0; ESIMS m/z 180 ([M+]⁺).

6. Preparation of 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6)

To a 100 mL, round bottom flask was charged3-(3-chloro-1H-pyrazol-1-yl)pyridine (2.00 g, 11.1 mmol) andconcentrated sulfuric acid (4 mL). This suspension was cooled to 5° C.and 2:1 concentrated nitric acid/sulfuric acid (3 mL, prepared by addingthe concentrated sulfuric acid to a stirring and cooling solution of thenitric acid) was added dropwise at a rate such that the internaltemperature was maintained <15° C. The reaction was allowed to warm to20° C. and stirred for 18 hours. A sample of the reaction mixture wascarefully diluted into water, basified with sodium hydroxide (50 wt % inwater) and extracted with ethyl acetate. Analysis of the organic layerindicated that the reaction was essentially complete. The reactionmixture was carefully added to ice cold water (100 mL) at <20° C. It wasbasified with sodium hydroxide (50 wt % in water) at <20° C. Theresulting light yellow suspension was stirred for 2 hours and filtered.The filter cake was rinsed with water (3×20 mL) and dried to afford anoff-white solid (2.5 g, quantitative): mp 141-143° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 9.86 (s, 1H), 9.23-9.06 (m, 1H), 8.75-8.60 (m, 1H), 8.33(ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.64 (ddd, J=8.5, 4.7, 0.7 Hz, 1H); ¹³CNMR (101 MHz, DMSO-d₆) δ 149.49, 140.75, 136.02, 134.43, 132.14, 131.76,127.22, 124.31; EIMS m/z 224 ([M]⁺).

7. Preparation of 3-(3-chloro-4-amino-1H-pyrazol-1-yl)pyridine (2-7)

To a 100 mL, 3-neck round bottom flask was charged3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2.40 g, 10.7 mmol), aceticacid (4 mL), ethanol (4.8 mL) and water (4.8 mL). The mixture was cooledto 5° C. and iron powder (2.98 g, 53.4 mmol) was added portionwise over˜15 minutes. The reaction was allowed to stir at 20° C. for 18 hours anddiluted to 50 mL with water. It was filtered through Celite® and thefiltrate was carefully basified with a sodium hydroxide solution (50 wt% in water). The resulting suspension was filtered through Celite® andthe filtrate was extracted with ethyl acetate (3×20 mL). The organiclayers were combined, dried over sodium sulfate and concentrated todryness to afford a tan colored solid, which was further dried undervacuum for 18 hours (2.20 g, quantitative): mp 145-147° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.95 (dd, J=2.6, 0.8 Hz, 1 H), 8.45 (dd, J=4.7, 1.4 Hz,1 H), 8.08 (ddd, J=8.4, 2.7, 1.4 Hz, 1 H), 7.91 (s, 1 H), 7.49 (ddd,J=8.3, 4.7, 0.8 Hz, 1 H), 4.43 (s, 2 H); ¹³C NMR (101 MHz, DMSO-d₆) δ146.35, 138.53, 135.72, 132.09, 130.09, 124.29, 124.11, 114.09; EIMS m/z194 ([M]⁺).

Alternate synthetic route to3-(3-chloro-4-amino-1H-pyrazol-1-yl)pyridine (2-7): In a 250 mL 3-neckround bottom flask was added3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5.00 g, 21.8 mmol),ethanol (80 mL), water (40 mL), and ammonium chloride (5.84 g, 109mmol). The suspension was stirred under nitrogen stream for 5 minutesthen iron powder (4.87 g, 87.2 mmol) was added. The reaction mixture washeated to reflux (˜80° C.) and held there for 4 hours. After 4 hours areaction aliquot taken and the reaction had gone to full conversion asshown by HPLC analysis. Ethyl acetate (120 mL) and Celite® (10 g) wereadded to the reaction mixture and the mixture was let stir for 10minutes. The black colored suspension was then filtered via a Celite®pad and rinsed with ethyl acetate (80 mL) The filtrate was washed withsaturated sodium bicarbonate solution in water (30 mL) and the organiclayer was assayed. The assay gave 4.19 g (99% yield) of product. Theorganic solvent was removed in vacuo to give a brown colored crude solidthat was used without further purification.

8. N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2-8)

A 100 mL three-neck round bottom flask was charged with3-chloro-1(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) andethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 12.9 mmol) was added,followed by dropwise addition of acetic anhydride (0.629 g, 6.17 mmol)at <20° C. The reaction was stirred at 20° C. for 2 hours to afford asuspension, at which point thin layer chromatography analysis [Eluent:ethyl acetate] indicated that the reaction was complete. The reactionwas diluted with water (50 mL) and the resulting suspension wasfiltered. The solid was rinsed with water (10 mL) followed by methanol(5 mL). The solid was further dried under vacuum at 20° C. to afford thedesired product as a white solid (0.804 g, 66%): mp 169-172° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.05 (dd, J=2.8, 0.8 Hz, 1H), 8.82(s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.20 (ddd, J=8.4, 2.8, 1.4 Hz,1H), 7.54, (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); ¹³C NMR (101MHz, DMSO-d₆) δ 168.12, 147.46, 139.42, 135.46, 133.60, 125.47, 124.21,122.21, 120,16, 22.62; EIMS m/z 236 ([M]⁺).

9. Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (2-9)

In 125 mL 3-neck round-bottomed flask was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2.57 g, 9.44mmol), tetrahydrofuran (55 mL), and sodium tert-butoxide (1.81 g, 18.9mmol). The suspension was stirred for 5 minutes then ethyl bromide (1.41mL, 18.9 mmol), and tetrabutylammonium iodide (67 mg, 0.2 mmol) wereadded. The resulting gray colored suspension was then heated to 38° C.The reaction was analyzed after 3 hours and found to have gone to 81%completion, after 24 hours the reaction was found to have gone tocompletion. The reaction mixture was allowed to cool to ambienttemperature and quenched with ammonium hydroxide/formic acid (HCO₂H)buffer (10 mL). The mixture was then diluted with tetrahydrofuran (40mL), ethyl acetate (120 mL), and saturated sodium bicarbonate solutionin water (30 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×30 mL). The organic layers were combinedand silica gel (37 g) was added. The solvent was removed in vacuo togive a solid that was purified using semi-automated silica gelchromatography (RediSep Silica 220 g column; Hexanes (0.2%triethylamine)/ethyl acetate, 40/60 to 0/100 gradient elution system,flow rate 150 mL/minute) to give, after concentration, an orange solid(2.19 g, 88%).

10. Preparation of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine(2-10)

A solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1.8 g,6.80 mmol) in 1 N hydrochloric acid (34 mL) was heated at 80° C. for 18hours, at which point HPLC analysis indicated that only 1.1% startingmaterial remained. The reaction mixture was cooled to 20° C. andbasified with sodium hydroxide (50 wt % in water) to pH>9. The resultingsuspension was stirred at 20° C. for 2 hours and filtered. The filtercake was rinsed with water (2×5 mL), conditioned for 30 minutes, andair-dried to afford an off-white solid (1.48 g, 95%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.00 (dd, J=2.8, 0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.4 Hz, 1H),8.11 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.49 (ddd,J=8.4, 4.7, 0.8 Hz, 1H), 4.63 (t, J=6.0 Hz, 1H), 3.00 (qd, J=7.1, 5.8Hz, 2H), 1.19 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 146.18,138.31, 135.78, 132.82, 130.84, 124.08, 123.97, 112.23, 40.51, 14.28;ESIMS m/z 223 ([M+H]⁺).

Alternate synthetic route to3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (2-10):

To a 3-neck, 100-mL round bottom flask was chargedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5 g, 21.13 mmol)and tetrahydrofuran (50 mL). Sodium tert-butoxide (4.06 g, 42.3 mmol)was added (causing a temperature rise from 22° C. to 27.6° C.), followedby ethyl bromide (6.26 mL, 85 mmol). The reaction was stirred at 35° C.for 144 h at which point only 3.2% (AUC) starting material remained. Thereaction mixture was concentrated to give a brown residue, which wasdissolved in 1 N hydrochloric acid (106 mL, 106 mmol) and heated at 80°C. for 24 hours, at which point HPLC analysis indicated that thestarting material had been consumed. The reaction was cooled to 20° C.and basified with sodium hydroxide (50 wt % in water) to pH>9. Theresulting suspension was stirred at 20° C. for 1 hour and filtered. Thefilter cake was rinsed with water (25 mL) to afford a brown solid (5.18g). The resulting crude product was dissolved in ethyl acetate andpassed through a silica gel plug (50 g) using ethyl acetate (500 mL) aseluent. The filtrate was concentrated to dryness to afford a white solid(3.8 g, 80%).

11. Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(2-11)

A 100 mL three neck round bottom flask was charged with3-chloro-N-ethyl-1-(pyridine-3-yl)-1H-pyrazol-4-amine (5.00 g, 22.5mmol) and ethyl acetate (50 mL). Sodium bicarbonate (4.72 g, 56 1 mmol)was added, followed by dropwise addition of3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (5.95 g, 26.9 mmol) at<20° C. for 2 hours, at which point HPLC analysis indicated that thereaction was complete. The reaction was diluted with water (50 mL)(off-gassing) and the layers were separated. The aqueous layer wasextracted with ethyl acetate (20 mL) and the combined organic layerswere concentrated to dryness to afford a light brown solid (10.1 g,quantitative). A small sample of crude product was purified by flashcolumn chromatography using ethyl acetate as eluent to obtain ananalytical sample: mp 79-81° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (d,J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd,J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q,J=7.2 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.66-2.57 (m 2H), 2.57-2.44 (m,2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H). EIMS m/z 406([M]⁺).

12. Preparation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfoxo)propanamide(2-12)

N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (57.4 g, 141 mmol) was stirred in methanol (180 mL). To theresulting solution was added hydrogen peroxide (43.2 mL, 423 mmol)dropwise using a syringe. The solution was stirred at room temperaturefor 6 hours, at which point LCMS analysis indicated that the startingmaterial was consumed. The mixture was poured into dichloromethane (360mL) and washed with aqueous sodium carbonate (Na₂CO₃). The organic layerwas dried over sodium sulfate and concentrated under reduced pressure toprovide a thick yellow oil. The crude product was purified by flashcolumn chromatography using 0-10% methanol/ethyl acetate as eluent. Thepure fractions were combined and concentrated to afford the desiredproduct as an oil (42.6 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (dd,J=2.8, 0.7 Hz, 1H), 8.98 (s, 1H), 8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.24(ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.61(q, J=7.4, 7.0 Hz, 2H), 3.20-2.97 (m, 2H), 2.95-2.78 (m, 2H), 2.76-2.57(m, 2H), 2.58-2.45 (m, 2H), 1.09 (t, J=7.1 Hz, 3H); ESIMS m/z 423([M+H]⁺).

Example A Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae)(MYZUPE.)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of leaves, and the death of various tissues. It isalso hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress andzucchini among other plants. GPA also attacks many ornamental crops suchas carnations, chrysanthemum, flowering white cabbage, poinsettia androses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA usingprocedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-5—GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four posts with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inwater to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofthe cabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume acetone/methanol(1:1) solvent. Treated plants were held in a holding room for three daysat approximately 25° C. and ambient relative humidity (RH) prior tograding. Evaluation was conducted by counting the number of live aphidsper plant under a microscope. Percent Control was measured by usingAbbott's correction formula (W. S. Abbott, “A Method of Computing theEffectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows.

-   -   Corrected % Control=100*(X−Y)/X    -   where    -   X=No. of live aphids on solvent check plants and    -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE)and sweetpotato whitefly-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci)(BEMITA.)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recordedin the United States since the late 1800s. In 1986 in Florida, Bemisiatabaci became an extreme economic pest. Whiteflies usually feed on thelower surface of their host plant leaves. From the egg hatches a minutecrawler stage that moves about the leaf until it inserts itsmicroscopic, threadlike mouthparts to feed by sucking sap from thephloem. Adults and nymphs excrete honeydew (largely plant sugars fromfeeding on phloem), a sticky, viscous liquid in which dark sooty moldsgrow. Heavy infestations of adults and their progeny can cause seedlingdeath, or reduction in vigor and yield of older plants, due simply tosap removal. The honeydew can stick cotton lint together, making it moredifficult to gin and therefore reducing its value. Sooty mold grows onhoneydew-covered substrates, obscuring the leaf and reducingphotosynthesis, and reducing fruit quality grade. It transmittedplant-pathogenic viruses that had never affected cultivated crops andinduced plant physiological disorders, such as tomato irregular ripeningand squash silverleaf disorder. Whiteflies are resistant to manyformerly effective pesticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used at test substrate. The plants were placed in a room withwhitefly adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbliss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm.A hand-held Devilbliss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Pesticidal activity was measured by using Abbott'scorrection formula (see above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly- crawler (BEMITA) RatingTable Example Compound BEMITA MYZUPE Compound 2 C C Compound 3 C CCompound 2-11 A A Compound 2-12 A A

% Control of Mortality Rating 80-100 A More than 0-Less than 80 B NotTested C No activity noticed in this bioassay D

1.-8. (canceled)
 9. A process for preparing4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1)

comprising contacting 3-hydrazinopyridine•dihydrochloride

with alkyl methacrylate,

wherein R is (C₁-C₄) alkyl, in a (C₁-C₄) alkyl alcohol at a temperaturefrom about 25° C. to about 80° C. in the presence of an alkali metal(C₁-C₄) alkoxide.
 10. The process of claim 9, wherein the (C₁-C₄) alkylalcohol is selected from the group consisting of methanol, ethanol,propanol, butanol, and mixtures thereof.
 11. The process of claim 10,wherein the (C₁-C₄) alkyl alcohol is ethanol.
 12. The process of claim9, wherein the alkali metal (C₁-C₄) alkoxide is selected from the groupconsisting of sodium methoxide, sodium ethoxide, and mixtures thereof.13. The process of claim 9, wherein the (C₁-C₄) alkyl alcohol is ethanoland the alkali metal (C₁-C₄) alkoxide is sodium ethoxide.
 14. A processfor preparing 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine(2)

comprising contacting 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1)

with a chlorinating reagent in an organic solvent at a temperature ofabout 25° C. to about 100° C.
 15. The process of claim 14, wherein thechlorinating agent is selected from the group consisting of phosphorylchloride, phosphorus pentachloride, and mixtures thereof.
 16. Theprocess of claim 15, wherein the chlorinating agent is phosphorylchloride.
 17. The process of claim 14, wherein the chlorinating agent isused in about a 1.1 fold to about a 10 fold excess compared to4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one.
 18. A process for preparing3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3)

comprising contacting3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2)

with an oxidant in a solvent at a temperature of about 25° C. to about100° C.
 19. The process of claim 18, wherein the oxidant is selectedfrom the group consisting of copper(I) chloride in the presence ofoxygen, potassium ferricyanide, and manganese (IV) oxide.
 20. Theprocess of claim 18, wherein the oxidant is used in about a 1.5 fold toabout a 15 fold excess compared to3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine.
 21. Theprocess of claim 18, wherein the solvent is selected from the groupconsisting of water, N,N-dimethylformamide, N-methylpyrrolidinone,dichloromethane, tert-butanol, acetonitrile, toluene, and mixturesthereof.
 22. The process of claim 18, wherein the oxidant is copper(I)chloride in the presence of oxygen, and the solvent is selected from thegroup consisting of N,N-dimethylformamide, N-methylpyrolidinone, andmixtures thereof.
 23. The process of claim 18, wherein the oxidant ispotassium ferricyanide, and the solvent is water.
 24. The process ofclaim 18, wherein the oxidant is use manganese (IV) oxide, and thesolvent acetonitrile.
 25. A process for preparing3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (4)

comprising contacting 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3)

with an oxidant in a polar protic solvent at a temperature of about 50°C. to about 100° C.
 26. The process of claim 25, wherein the oxidant ispotassium permanganate or sodium permanganate.
 27. The process of claim25, wherein the oxidant is used in about a 2.5 fold to about a 4.5 foldexcess compared to 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine. 28.The process of claim 25, wherein polar protic solvent does notsubstantially react with the oxidant.
 29. The process of claim 28,wherein the polar protic solvent is selected from the group consistingof water, tert-butanol, tert-amyl alcohol, and mixtures thereof.
 30. Theprocess of claim 25, wherein the oxidant is sodium permanganate, and thepolar protic solvent is a mixture of water and tert-butanol.
 31. Aprocess for preparing 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

comprising contacting 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylicacid (4)

with copper oxide in a polar aprotic solvent at a temperature of about80° C. to about 180° C. to provide 3-(3-chloro-1H-pyrazol-1-yl)pyridine(5b).
 32. The process of claim 31, wherein the copper oxide is ligatedwith a bidentate ligand.
 33. The process of claim 32, wherein thebidentate ligand is tetramethyl ethylenediamine.
 34. The process ofclaim 31, wherein the copper oxide is copper (I) oxide or copper (II)oxide.
 35. The process of claim 31, wherein the copper oxide is used inabout 5 wt % to about 20 wt % based on3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid.
 36. The processof claim 31, wherein the polar aprotic solvent is selected from thegroup consisting of N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, and mixtures thereof.
 37. The process of claim31, wherein the copper oxide is copper (I) oxide, and the polar aproticsolvent is N,N-dimethylacetamide.